In the retina, the sign-inverting synapse between photoreceptors and On bipolar cells is the foundation for the ON pathway in vision. The synapse is sign-inverting because glutamate, released in darkness by rod and cone photoreceptors, hyperpolarizes the membrane of ON bipolar cells. Hyperpolarization arises when binding of glutamate to the metabotropic receptor mGluR6 on the dendrites of the ON bipolar cell activates a G protein (Go), which then shuts off a synaptic transduction current, most likely through a membrane-delimited pathway. The channel underlying the transduction current allows a mixture of cations to flow through it; as a result of this ion selectivity, the ON bipolar cell to depolarizes when light shuts off transmitter release from photoreceptors and allows these channels to open. We have found that the size of the transduction current is very plastic, and can be modulated by at least two factors: Ca2+ and cGMP. We have shown previously that Ca2+, by activating the Ca2+/calmodulin-dependent phosphatase calcineurin, down-regulates the transduction current. On the other hand, preliminary data from my laboratory suggests that cGMP up-regulates the transduction current by activating the cGMP-dependent kinase PKG. Both forms of regulation appear to depend upon the activity of the mGluR6 cascade. When there is enough glutamate available to bind most or all of the mGluR6 receptors and hold all of the transduction channels closed (high activity), we find that the channels become up-regulated so that brief periods of glutamate removal result in large currents. The opposite holds when there is less glutamate available. In the first aim we will test the hypothesis that this form of "use-dependence" contributes to adaptive changes in sensitivity that are a hallmark of the retina. The second aim will focus specifically on how cGMP regulates the transduction current. We will ask whether modulation of postsynaptic sensitivity is lost in animals lacking specific isoforms of PKG, or when PKG activity is pharmacologically inhibited. We will also see immunohistochemical evidence for the expression of PKG in ON bipolar cells. The third aim will test the hypothesis that kinetics of desensitization of the transduction current contribute to the kinetics of light responses in ON cells. Results from these studies will provide insight into the fundamental mechanisms that regulate sensitivity and dynamic range in the visual system.